Frequently, sampling of biological fluids from a subject, for example to determine the concentration of a substance or substances in the biological fluid for purposes of diagnosis, and/or delivery of drugs to a subject, for example to control delivery rate and/or adequacy of drug level, requires sustained or repeated sampling or delivery over a defined, and often extended, time period.
By way of example, the availability of chemical substances in the body to tissue is often subject to temporal fluctuations, such that a series of samples taken over time from the biological fluid would reveal a distribution of concentration values of the substance. In general, it is the net effect of this temporal distribution of concentration values over some time interval, rather than the value that is observed at any particular moment, that is of interest. One measurement of the net effect of temporal fluctuations in substance concentration over some time interval is the summation of momentary concentration values over that interval, or the "time integral" of concentration. The time integral, divided by the length of the time interval over which it was obtained, results in the average concentration of the substance of interest over that time interval.
The time interval that may be of interest varies according to the context of the measurement, but is frequently on the order of hours. Time integrated measurements on a scale of hours reflect a more enduring state of the organism than measurements representative only of momentary conditions.
Frequently, concentrations of a substance of interest are measured in blood, rather than saliva, since blood is the primary means of transporting most substances within the body. However the concentration of a substance of interest in blood is not always the same as the concentration available to other tissues, the latter typically being of greater interest in diagnostics. This is so because substances must diffuse across cell membranes in order to arrive at other tissues from the blood, and because frequently the substance of interest exists in multiple forms in the blood, not all of which are equally able to cross cell membranes.
In particular, the substance of interest may form associations with other substances (such as proteins) that have much lower ability to permeate cell membranes than has the substance of interest in its free, or unbound, form. In such a case, the concentration of the substance of interest available to tissues other than blood may be much more closely related to the concentration of the free form than to the associated, or bound, forms, or aggregates thereof. Frequently, the bound forms are very much more abundant than the free form.
Moreover, saliva has many advantages as a medium for assessing the concentrations of substances available to tissue in humans. Not only is saliva much more convenient to collect than blood or urine, but levels of many substance of interest in saliva generally reflect the concentrations of the free fractions of those substances in blood plasma. To the degree that saliva concentration of a substance of interest mirrors that of the free fraction of the substance in plasma, the saliva concentration provides more direct information about the availability of the substance to tissue.
There are, however, some significant problems in the interpretation of salivary concentrations of substances. These problems are due to two factors. First, in practice, saliva is often contaminated to some extent with blood or blood plasma, thus including the bound fraction of the substance of interest that is essentially unavailable to tissue. Second, the concentrations of substances in saliva fluctuate over time just as in other body fluids.
Consequently, the interpretation of substance concentrations measured in saliva samples is difficult, since it is generally not known whether there was some degree of blood plasma contamination of saliva, or whether the concentration observed reflected a momentary fluctuation or a longer-enduring state.
It would thus be desirable to provide saliva sampling devices and methods that can be used to obtain a sample of a substance of interest, such that the abundance of the substance of interest in this sample specifically reflects the time integral of the concentration of the free fraction of the substance of interest in saliva (to the exclusion of bound forms) over some known time interval, and that eliminate or minimize measurement inaccuracy caused by blood or blood plasma contamination of saliva.
While devices and/or methods have been heretofore suggested and/or utilized for collecting saliva samples intraorally (see, for example, U.S. Pat. Nos. 4,774,692 and 4,817,632), such devices and methods are not particularly adapted to gathering primarily the substance of interest, rather being directed to gathering saliva samples. Where some filtration of saliva samples has been provided (for example by way of a porous membrane surrounding an osmotically active substance as shown in U.S. Pat. No. 4,817,632), the concentration of a substance of interest derived from analysis of a saliva sample thus collected has no obvious relation to the average concentration of the free fraction of the substance over the interval of use, or even to the concentration of such substance at any identifiable moment within the interval, but instead most closely approximates the concentration present during periods of rapid fluid uptake inherent in such heretofore known devices.
Devices and methods have also been heretofore suggested and/or utilized for the purpose of measuring the concentration of a substance of interest in interstitial fluid, and have therefore been designed to be implantable under the skin of an animal (see U.S. Pat. Nos. 4,798,207 and 4,594,326, by the inventor of the herein disclosed invention). Such devices have of necessity provided means for inserting and withdrawing the binding composition utilized to capture the substance of interest in the device, and required construction utilizing materials compatible with in vivo implantation.
While the device and methods of this invention share many of the general principles discussed in U.S. Pat. No. 4,594,326 (relevant portions of the disclosure of which are incorporated herein by this reference), further improvements to adapt the method therein discussed for use in measuring substances of interest in saliva could be utilized.
In particular, means of accumulating a specific substance of interest intraorally from saliva in such a way that the amount accumulated during some time interval is substantially directly representative of the average concentration of the free fraction of the substance (and thus available to other tissue) in the fluid during that time interval could be utilized. In such a case, it would be desirable that such means not depend upon the net accumulation of saliva fluid, nor be limited by volumetric capacity of a device for such accumulation.
By way of further example (in the case of sustained drug delivery), sustained intraoral delivery of an antibiotic such as tetracycline, for the purpose of treating a periodontal infection or the like, would be desirable. In such a case, therapeutic drug levels could be maintained in the oral cavity over a long period of time. This would be advantageous from the point of view of maintaining adequate drug levels at the site of the infection, without exposing other tissues to such high levels of drug, thereby minimizing undesirable side effects. Devices and methods for such sustained intraoral drug delivery could thus be utilized which regulate the transfer of the drug into saliva.